Peroxisomal disorders affecting phytanic acid α-oxidation: a review

Peroxisomes are involved in the synthesis and degradation of complex fatty acids. They contain enzymes involved in the α-, βand ω-oxidation pathways for fatty acids. Investigation of these pathways and the diseases associated with mutations in enzymes involved in the degradation of phytanic acid have led to the clarification of the pathophysiology of Refsum’s disease, rhizomelic chondrodysplasia and AMACR (α-methylacyl-CoA racemase) deficiency. This has highlighted the role of an Fe(II)and 2-oxoglutaratedependent oxygenases [PhyH (phytanoyl-CoA 2-hydroxylase), also known as PAHX], thiamin-dependent lyases (phytanoyl-CoA lyase) and CYP (cytochrome P450) family 4A in fatty acid metabolism. The differential regulation and biology of these pathways is suggesting novel ways to treat the neuro-ophthalmological sequelae of Refsum’s disease. More recently, the discovery that AMACR and other peroxisomal β-oxidation pathway enzymes are highly expressed in prostate and renal cell cancers has prompted active investigation into the role of these oxidation pathways and the peroxisome in the progression of obesityand insulin resistance-related cancers. Introduction Peroxisomes are cellular organelles involved in biosynthetic and degradative functions [1], which, like mitochondria, may have originated from ancient commensal bacteria. Anabolic functions of peroxisomes include the biosynthesis of cholesterol and plasmalogens for cell and neuronal membranes [2]. They degrade unsaturated and aromatic fatty acids including bile acids. Peroxisomes also contain an analogous fatty acid β-oxidation pathway to that found in mitochondria and also specific enzymes for the α-oxidation of 3-methyl branched fatty acids including PA (phytanic acid) [3]. Peroxisomes Peroxisomes are able to catabolize a wide variety of lipids, including long-chain (C12–C18), very-long-chain (C20–C26) and ultra-long-chain (C28–C38) fatty acids, unsaturated fatty acids, bile acid intermediates, 2-methyl fatty acids (e.g. pristanic acid), 3-methyl fatty acids (e.g. PA) and diethyl ether phospholipids [3]. The primary catabolic route for peroxisomal lipids is the β-oxidation pathway. Although different enzymes are used, it seems that β-oxidation in peroxisomes is roughly analogous to that occurring in mitochondria. Human peroxisomes apparently contain two β-oxidation systems: an inducible pathway that metabolizes long-chain fatty acids and a constitutive pathway that oxidizes pristanic and bile acids